Topical anti-inflammatory agent

ABSTRACT

METHODS AND COMPOSITIONS FOR TOPICAL APPLICATION OF AN INDOMETHACIN-METHYLSALICYLATE FORMULATION FOR THE TREATMENT OF INFALMMATION.

United States Patent 3,629,412 TOPICAL ANTI-INFLAMMATORY AGENT Robert H.Silber, Westfield, Kane L. Kelley, Roselle, and Idamae G. Trenner,Westfield, N.J., assignors to Merck & Co., Inc., Rahway, NJ. No Drawing.Filed Sept. 19, 1969, Ser. No. 859,591 Int. Cl. A61k 27/00 US. Cl.424-232 4 Claims ABSTRACT OF THE DISCLOSURE Methods and compositions fortopical application of an 1ndomethacin-methylsalicylate formulation forthe treatment of inflammation.

This invention is concerned with the topical application CHaO $011200 OH\N vCH3 Indomethacins unique chemical structure differentiates it fromthe salicylates, corticosteroids, phenylbutazonelike compounds andcolchicine. Unlike corticosteroids, it has no effect on pituitary oradrenal function and accordingly does not manifest the adverse sideeffects associated therewith. Oral administration of indomethacin haspreviously been reported as eflective in relieving pain, reducing feverand providing increased mobility in patients with inflammatory disordersincluding those of a rheumatic nature. When orally administered, thedrug behaves as a systemic medicine and passes into the blood stream forgeneral distribution in the body. As is the case with numerous otherdrugs, not everyone can satisfactorily accept this drug via the oralmode of administration, particularly over extended periods of therapy.

It is one object of this invention to provide a method of administeringindomethacin which avoids the disadvantages of oral administration.

Another object of this invention is to provide a carrier vehicle for thetopical application of indomethacin whereby both local and systemictreatment of inflammation in mammals, including warm-blooded animals,such as mice, rats, horses, dogs, cats, etc., is achieved.

In accordince with this invention it is found that indomethacin can beadministered by applying topically a so lution of the drug in amethylsalicylate vehicle. In addition to providing highly effectiverelief with respect to local inflammation, topical application of theindomethacin-methylsalicylate formulation results in systemic treatmentof inflammatory disorders. It is believed that the skin, in the presenceof the topical formulation, acts 3,629,412 Patented Dec. 21, 1971 as areservoir absorbing large amounts of the drug and releasing it slowly toother tissues. In this respect it is believed that the skin may act as adepot or reservoir for the indomethacin. It is theorized that themethylsalicylate, in addition to assisting in the solubilization of thedrug, also enhances the absorption of indomethacin through the skin andaccordingly permits the drug to be employed topically for inflammationof the tendons and joints, etc.

Methylsalicylate has been widely used for many years, formerly under thename of oil of Wintergreen, for its counter-irritant action in variousliniments. Methylsalicylate is produced synthetically or is obtained bymaceration from the leaves of Gaultheria procumbeus or from the bark ofBetula leuta. It has been reported that it is impolssible to distinguishbetween the synthetic and natural 01 Although the indomethacin may beadvantageously applied topically to the skin with only methylsalicylateas the vehicle carrier, further inclusion in such formulation ofnon-toxic solvents, surfactants, emollients, etc., which are misciblewith the methylsalicylate, may be employed. Included among the materialssuitable for this purpose are the following: ethanol, isopropyl alcohol,2- 'octyl dodecanol, methyl pyrrolidone, glycerin, squalene, squalone,isopar M (hydroxyphenyldialiphatic amine), isopropyl myristrate,Ceraphyl 230 (diisopropyl adipate), acetulan (acetylated lanolinalcohols), polyethylene glycol, dimethylsulfoxide, diethyl phthalate,dimethylacetamide, polysorbate and diisopropyl adipate.

Mixtures of the above ingredients may also be combined with theindomethacin-methylsalicylate combination.

In addition, one may combine topical anaesthetics and analgesics withthe indomethacin-methylsalicylate formulation. Representative members ofthis class that may be combined with the formulation include alkaloidssuch as cocaine, benzocaine, procaine, dibucaine, lidocaine, larocaine,cyclomethylcaine, naepine, etc. If desired, the nontoxic solvents,surfactants, etc., described above may also be included in thisformulation.

The concentration of the indomethacin in the methylsalicylate is notcritical and will depend, as one skilled in the art will appreciate,upon a variety of factors including the age, body weight, the severityof the disorder being treated, etc.

Topical application of a formulation containing from about .1 to 20 mg.of indomethacin per ml. of methylsalicylate vehicle is eflective in thetreatment of inflammatory disorders with optimal effects being obtainedwith topical formulations containing from about 1 to about 10 mg. ofindomethacin per ml. of methylsalicylate vehicle.

As indicated above, the amount applied topically for either localtreatment or a systemic response will vary depending upon a number ofconsiderations. In this regard, the art further appreciates that in manyinstances a relatively strong concentration or more frequent applicationof a weaker concentration may be equally effective. The objective in allcases is to obtain the maximum therapeutic response with minimum dosage.

For example, topical application daily of from about .5 mg./kg. to 20mgs./kg. of the formulations described above (based upon the weight ofindomethacin) are effective in the treatment of local and systemicinflammation.

As indicated above, it is highly desirable to add a substance such asethanol or propanol to the indomethacinmethylsalicylate to assist in thesolubilization of the drug. It will be appreciated that surfactants andsolubilization agents other than alcoholic materials may be used in thisrespect. Where it is found desirable to add an agent of this nature,this ingredient may be present in amounts ranging from about 50% toabout based upon the total weight of the methylsalicylate-containingvehicle. The concentration of topical analgesic or anaesthetic may varyfrom about 5% to about 20% based upon the total weight of themethylsalicylate containing vehicle.

In addition to compositions containing indomethacin andmethylsalicylate, the following are representative examples of vehicleformulations which include solubilizers, analgesics, anaesthetics, etc.:

Percent Ethanol 54 Ceraphy1-230 36 Methyl salicylate 10 containing 2.5mg. Indomethacin per ml. of vehicle.

Percent Ethanol 50 Methyl salicylate l Polysorbate 80 15 Ceraphyl-23OWater 20 containing 2.0 mg. of Indomethacin per ml. of vehicle.

Percent Ethanol Methyl salicylate 10 Squalene 80 containing 2.0 mg. ofIndomethacin per ml. of vehicle.

Percent Ethanol 17 Squalene 68 Methyl salicylate containing 2.0 mg. ofIndomethacin per ml. of vehicle Percent Ethanol 5 Methyl salicylate 5'Squalane 90 containing 10.0 mg. of Indomethacin per ml. of vehicle.

Percent Ethanol 10 Methyl salicylate 30 Squalane 60 containing 2.5 mg.of Indomethacin per ml. of vehicle.

Percent Isopropyl alcohol 28.34 Methyl salicylate 1.66 Isopar M 70containing 3.2 mg. of Indomethacin per ml. of vehicle.

Percent Isopropyl alcohol 25 Methyl salicylate 5 Isopar M 70 containing6.2 mg. of Indomethacin per ml. of vehicle.

Percent Isopropyl Alcohol 15 Methyl Salicylate 15 Isopar M 70 containing2.0 mg. of Indomethacin per ml. of vehicle.

Percent Ethanol 25 Methyl salicylate 75 containing 20 mg. ofIndomethacin and 10 mg. of benzocaine per ml. of vehicle.

Percent Methyl salicylate l0 Ethanol containing 5.0 mg. of Indomethacinand 2.0 mg. of benzocaine per ml. of vehicle.

The formulations of this invention may be prepared employing techniqueswell known in the art. For example, solutions of up to approximately 10%may be prepared by mixing the indomethacin in methylsalicylate andwarming with tap water or in a water bath (approximately 60 C.). Theadditional ingredients to be included in the formulation may be combinedtherewith. In addition to solutions, the formulation of the inventionmay be administered topically as lotions, creams, ointments, salves,etc.

The anti-inflammatory reaction to the topical administration ofindomethacin in a methylsalicylate vehicle is nonspecific and occurswhether the injuring agent or stress be physical or chemical. Moreover,a favorable response is induced by the topical application of theindomethacin-methylsalicylate formulation not merely when theinflammatory reaction is localized but also when the condition is moreextensive and the reaction is systemic. Accordingly, it should be notedthat topical application of indomethacin in a methylsalicylateformulation provides not merely beneficial effects in the treatment ofinflammatory disorders affecting the skin, but relief is obtained in thetreatment of diseases involving inflammation of the muscles and joints.

As indicated previously, the indomethacin-methylsalicylate combinationmay be administered topically to achieve local and/or systemic effect.This is in sharp distinction with conventional orally administeredanti-inflammatory agents which are either ineffected in relieving localdisorders when applied topically; or if effective in the treatment oflocal inflammation, the topical administration of the drug is ofnegligible significance in the systemic treatment of conditionsrequiring such therapy. For example, the literature reports that thenormal, conventional local application of hydrocortisone ointment doesnot produce an effective systemic response. Systemic therapy is ofcourse of preferred when the inflammation involvement is extensive.Topical application of the formulation of this invention provides theunexpected and unobvious advantages of both local and systemic therapy.

What is claimed is:

1. The method of administering indomethacin to a patient afilicted withinflammation which comprises the topical application of a formulationcomprising an effective amount of indomethacin in methylsalicylate.

2. The method of claim 1 wherein the formulation contains a solubilizer.

3. The method of claim 2 wherein the solubilizer is an alcohol.

4. The method of claim 3 which further contains an anaesthetic oranalgesic.

Merck Index, 7th ed. (1960), p. 683. Chem. Absts., vol. 67 (1967),81065H.

STANLEY I. FRIEDMAN, Primary Examiner US. Cl. X.R.

